Project summary: This project is to investigate spatiotemporal interactions between neural activities and hemodynamic changes in the retina, and to explore quantitative mapping of retinal neurovascular coupling defects caused by neurodegenerative diseases. Retinal neurodegenerative diseases, such as age-related macular degeneration (AMD), retinitis pigmentosa (RP), diabetic retinopathy (DR) and glaucoma, can produce severe vision losses if medical interventions cannot be provided promptly. As one part of the central never system (CNS), the retina is also targeted by other neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases which are the major cause of dementia. Early detection of these neurodegenerative diseases is essential for better study and development of preventive strategies. Functional imaging of neurovascular coupling defects promises early detection of neurodegeneration. Direct access to the brain for high-resolution examination of neurovascular coupling defects is difficult. The retina opens a window for high-resolution study of neurovascular coupling defects. This project is to explore spatiotemporal mapping of three-dimensional (3D) interactions between neural activities and hemodynamic changes. The first aim of this project is to refine our existing spectral-domain optical coherence tomography (OCT), and to extend our recently demonstrated swept- source parallel OCT to a multi-functional parallel OCT (MF-P-OCT) instrument, which will provide 5 m spatial resolution and 5 ms OCT volume speed. The MF-P-OCT will enable functional OCT of stimulus-evoked neural activities and functional OCT angiography (OCTA) of microvascular responses simultaneously. The second aim is to investigate retinal neurovascular defects in retinal degeneration rd10 and APPswe/PSEN1dE9 mice, in which outer retina (photoreceptor) and inner retina (ganglion) are degenerated first, respectively. Morphological OCT and OCTA features, including retinal thickness, blood vessel caliber (BVC), blood vessel tortuosity (BVT), vessel perimeter index (VPI), and blood vessel density (BVD) will be quantitatively compared in normal and diseased mice. Comprehensive analysis of stimulus-evoked vasodilation, transient blood and oxygen changes will be used for in-depth understanding of blood/oxygen consumption at the capillary level in normal and diseased retinas. Concurrent monitoring of stimulus-evoked intrinsic optical signals (IOSs) correlated with neural activity (i.e., neural-IOS) and vascular response (i.e., hemodynamic-IOS) will be used for objective evaluation of spatial and temporal characteristics of neurovascular coupling interactions in the retina. The key success criterion of this project is to verify functional detection of neurovascular coupling defects (i.e., distorted stimulus-evoked hemodynamics at capillary level), before the appearance of detectable morphological abnormalities (i.e., neuronal loss and vessel dropout). Success in this project will produce a noninvasive imaging platform for high- resolution and objective assessment of functional relationship between neural degeneration and vascular pathology, promoting early detection and therapy development of neurodegeneration diseases.